CCR8/CCL1 and CXCR3/CXCL10 axis mediated memory T cell activations in recalcitrant drug-induced hypersensitivity patients

Tsu-Man Chiu; Chun-Bing Chen; Chun-Wei Lu; Rosaline Chung-Yee Hui; Min-Hui Chi; Ya-Ching Chang; Jennifer Wu; Kuan-Yu Chen; Yang Yu-Wei Lin; Pei-Chi Lo; Tsai-Ching Hsu; Chuang-Wei Wang; Wen-Hung Chung

doi:10.1093/bjd/ljae375

CCR8/CCL1 and CXCR3/CXCL10 axis mediated memory T cell activations in recalcitrant drug-induced hypersensitivity patients

Br J Dermatol. 2024 Nov 6:ljae375. doi: 10.1093/bjd/ljae375. Online ahead of print.

Authors

Tsu-Man Chiu^{1

2

3}, Chun-Bing Chen^{4

5

6

7

8

9

10

11

12}, Chun-Wei Lu^{4

6

7

8

9

11}, Rosaline Chung-Yee Hui^{4

7}, Min-Hui Chi^{4

7

13}, Ya-Ching Chang^{4

7}, Jennifer Wu^{4

7

8}, Kuan-Yu Chen^{4

7}, Yang Yu-Wei Lin⁴, Pei-Chi Lo⁴, Tsai-Ching Hsu^{2

14

15}, Chuang-Wei Wang^{4

5

6

12

16}, Wen-Hung Chung^{4

5

6

7

8

10

17

18

19}

Affiliations

¹ Department of Dermatology, Chung Shan Medical University Hospital, Taichung, Taiwan.
² Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
³ School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
⁴ Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, Tucheng and Keelung, Taiwan.
⁵ Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taiwan.
⁶ Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China.
⁷ College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁸ Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan.
⁹ Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
¹⁰ Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan.
¹¹ School of Medicine, National Tsing Hua University, Hsinchu, Taiwan.
¹² Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan.
¹³ Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
¹⁴ Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan.
¹⁵ Immunology Research Center, Chung Shan Medical University, Taichung, Taiwan.
¹⁶ Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
¹⁷ Department of Dermatology, Beijing Tsinghua Chang Gung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.
¹⁸ Department of Dermatology, Ruijin Hospital; School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
¹⁹ Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan.

PMID: 39503255
DOI: 10.1093/bjd/ljae375

Abstract

Background: As a drug-induced hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) is potentially fatal. Most patients with DRESS recover within a few weeks; however, some patients may suffer from a prolonged disease course and develop autoimmune sequelae.

Objective: We investigated the immune mechanism and therapeutic targets of patients with recalcitrant DRESS with a prolonged disease course.

Methods: A total of 32 patients with recalcitrant DRESS with a prolonged treatment course ≥8 weeks, 28 patients with short-duration DRESS with a treatment course <2 weeks, and 26 healthy individuals were enrolled in the study for analysis.

Results: Bulk transcriptome results demonstrated that mRNA expression levels of CCR8 and CXCR3 were significantly increased in the blood samples from patients in the acute stage of prolonged DRESS (adjusted p-values: CCR8=1.50×10-9 and CXCR3=2.60×10-4, respectively, for comparison of patients with prolonged DRESS to the healthy donor group). Serum and skin lesional concentrations of CCL1 and CXCL10, as the ligands of CCR8 and CXCR3, respectively, were significantly elevated in patients with prolonged DRESS as compared to those patients with short-duration DRESS. The results from high-parameter flow cytometry and autoantibody screening also identified significant escalations of CD8+ GNLY+CXCR3+effector memory T cells, CD8+central memory T cells, CD4+CCR8+Th2 cells, and IgG-anti-HES6 autoantibodies in patients with prolonged DRESS. Furthermore, in vitro blocking assays revealed that JAK inhibitors (mainly tofacitinib and upadacitinib) significantly decreased the release of CCL1 and CXCL10, and some patients with prolonged DRESS were successfully treated with JAK inhibitors.

Conclusions: JAK inhibitors (tofacitinib and upadacitinib) were associated with decreased concentrations of CCL1 and CXCL10, suggesting that they may attenuate CCR8/CCL1- and CXCR3/CXCL10-axis-mediated memory T cell activation, which contribute to disease pathogenesis for patients with recalcitrant DRESS and a long-term treatment course.